Triazole compounds

ABSTRACT

THIS INVENTION RELATES TO NOVEL COMPOUNDS OF THE FORMULA   3-(5-(NO2-)FUR-2-YL),4-R1,5-(R2-N(-R3)-)-4H-1,2,4-TRIAZOLE   WHEREIN R1 REPRESENTS LOWER ALKYL; R2 IS HYDROGEN OR A LOWER ALKYL; R3 IS HYDROGEN OR A LOWER ALKYL OR A RADICAL OF THE FORMULA-COR4, (WHEREIN R4 IS HYDROGEN OR AN ALKYL CONTAINING FROM 1 TO 3 CARBON ATOMS, OR A HALOGEN-SUBSTITUTED ALKYL CONTAINING FROM 1 TO 3 CARBON ATOMS). IT ALSO RELATES TO THERAPEUTICALLY USEFUL SALTS OF THESE COMPOUNDS AND THE DISCLOSED METHODS OF PREPARING SUCH COMPOUNDS. THE NOVEL COMPOUNDS ARE USEFUL AS INFECTION COMBATTING AGENTS, AND ESPECIALLY USEFUL AS URINARY TRACT ANTISEPTICS.

United States Patent 3,557,137 TRIAZOLE COMPOUNDS Kurt T. J. Skagius and Eva B. Akerblom, Uppsala, Sweden, assignors to Pharmacia Aktiebolag, Uppsala, Sweden, a corporation of Sweden No Drawing. Continuation-impart of application Ser. No. 432,412, Feb. 12, 1965. This application Aug. 20, 1968, Ser. No. 753,883

Int. Cl. C07d 55/06 US. Cl. 260308 Claims ABSTRACT OF THE DISCLOSURE This invention relates to novel compounds of the formula HCCH N-N R2 out Ll aN wherein R represents lower alkyl; R is hydrogen or a lower alkyl; R is hydrogen or a lower alkyl or a radical of the formula -COR (wherein R is hydrogen or an alkyl containing from 1 to 3 carbon atoms, or a halogen-substituted alkyl containing from 1 to 3 carbon atoms). It also relates to therapeutically useful salts of these compounds and the disclosed methods of preparing such compounds. The novel compounds are useful as infection combatting agents, and especially useful as urinary tract antiseptics.

CROSS-REFERENCE TO RELATED CASE Reference is made to our prior copending application Ser. No. 432,412 filed Feb. 12, 1965 and now abandoned, of which this is a continuation-in-part application.

THE PRESENT INVENTION) This invention relates to novel compounds of the formula wherein R represents lower alkyl; R is hydrogen or a lower alkyl; R is hydrogen or a lower alkyl or a radical of the formula COR (wherein R is hydrogen or an alkyl containing from 1 to 3 carbon atoms, or a halogensubstituted alkyl containing from 1 to 3 carbon atoms).

As alkyl groups in the compounds of the above Formula I may be mentioned the following: methyl, ethyl, n-propyl, and isopropyl.

As acyl groups in the compounds of the above Formula I may be mentioned: formyl, acetyl, propionyl, chloroacetyl, dichloroacetyl, 2 chloropropionyl, and bromoacetyl.

When at least one of the radicals R and R is hydrogen,

the compounds of the above Formula I may exist in their tautomeric forms. The present invention also encompasses corresponding compounds when being in these forms.

Examples of specific compounds that are contemplated by this invention would include:

3,557,137 Patented Jan. 19, 1971 "ice PREPARATION OF THE NOVEL COMPOUNDS wherein R R and R are the same as specified with regard to Formula I. According to the invention, a compound of the Formula II is treated with a nitrating agent and the compound thus formed is, if desired, reacted with a base or, if it does not contain an acyl group, with an acid to produce the corresponding therapeutically useful salt.

When the compound of the Formula I contains an acyl group, the latter may be split oil? by hydrolysis.

As a nitrating agent may be mentioned mixtures of concentrated nitric acid with concentrated sulphuric acid or concentrated acetic acid as dehydrating agents.

The compounds of Formula II may readily be obtained by ring closure of 2-furoylaminoguanidines and, if desired, subsequent acylation of the products obtained.

The ring closure can be effected either by heating or treating the 2-furoylaminoguanidine under basic conditions, especially in aqueous solution containing an alkaline reacting substance.

In the nitration of the compounds of the Formula II, it is frequently valuable to use the acylated intermediates and, if desired, remove the acyl group by hydrolysis. The presence of an acyl group will as a rule increase the yield and give a purer product.

As examples of acylating agents may be mentioned anhydrides and halides of acids having the formula R 00 OH wherein R CO represents the acyl group to be introduced.

As examples of hydrolysing agents may be mentioned inorganic acids such as hydrochloric and sulphuric acids. The hydrolysing reaction may be carried out in the presence of organic solvents, such as lower alkanols, ketones, acids, and ethers. It may be carried out with or without isolation of the nitrated acyl-derivatives.

EXAMPLE I (a) Preparation of 2-methyl-l-furoylaminoguanidine 1 mole of furoylhydrazine and 1 mole of N-methyl-S- methylisothiourea hydroiodide were dissolved in 50 ml. of Water and 500 ml. of 2 M sodium hydroxide. Reaction occurred at room temperature with formation of a precipitate of Z-methyl-l-furoylaminoguanidine. A reaction time of about 120 hours was necessary to get a yield of M.P. ISO-153 C. (decomp.) (Found (percent): C, 45.9; H, 5.9; N, 30.4. Calc. for C H N O (182.1) (percent): C, 46.2; H, 5.5; N, 30.8.)

3 (b) Preparation of 3-amino-5-(2-furyl)-4-methyl- 1,2,4-triazole O IUIH 24.6 g. (0.135 mole) of 2-methyl-l-furoylaminoguanidine was dissolved in dimethylformamide and the solution was boiled for 1 hour. By cooling, 10.7 g. of 3-amino5-(2- furyl)-4-methyl-1,2,4-triazole precipitated. M.P. 240.5 243, 5 C. Themother liquor was evaporated and the residue was treated with ml. of 2 M sodium hydroxide leaving a further 1.5 g. of the same product. (Found (percent): C, 51.3; H, 5.1; N, 34.0. Calc. for C H N O (164.1) (percent): C, 51.2; H, 4.9; N, 34.1.)

By neutralization of the alkaline solution 6 g. of 5-(2- furyl)-3-methylamino-1,2,4-triazole precipitated.

' (c) Preparation of 3-acetylamino-5-(2-furyl)-4-rnethyl- 1,2,4-triazole N N N N m JM A020 l flN NHcoCH (13H: CH3

19 g. of 3-amino-5-(Z-furyl)-4-methyl-1,2,4-triazole was boiled with ml. of acetic anhydride for 2.5 hours. The solution was evaporated and the crude product treated with water. 19 g. of 3-acetylamino-5-(2-furyl)-4-methyl- 1,2,4-triazole was obtained. M.P. 2l7220 C. (decomp.). (Found (percent): C, 52.2; H, 5.0; N, 27.1. Calc. for C H N O (206.2) (percent): C, 52.4; H, 4.9; N, 27.2.)

((1) Preparation of 3-amino-4-methyl-5-(5-nitro-2-furyl)- 1,2,4-triazole The acetyl group was dehydrolyzed by boiling the comr pound in 33 ml. of 2 N hydrochloric acid and 100 ml. of water for 1% hours, thereby forming a clear solution. The latter was neutralized with ammonia to precipitate 3.1 g. of a flame-colored substance (72% calculated on the nitrated acetyl derivative). After recrystallization from a mixture of ethanol and dimethyl formamide, the substance was found to melt at 278.5279.5 C. with decomposition.

EXAMPLE 2 (a) Preparation of 4-ethyl-3-ethylamino-5-(2-furyl)- 1,2,4-triazole 25.5 g. (0.1 mole) of 1-amino-2,3-diethylguanidine hydroiodide and 13 g. (0.1 mole) of furoyl chloride were melted together at 100 C. for 35 min. The melt was cooled and recrystallized from acetonitrile. 19.8 g. of 2,3- diethyl-l-furoyl-aminoguanidine hydroiodide were obtained (M.P. 176-178 C.). This substance Was cyclized by boiling in ml. of 2 M sodium hydroxide for 1 hour. An oil precipitated which crystallized by cooling. The product was recrystallized from acetone giving 11.1 g. (54%) of 4-ethyl-3-ethylamino-5-(3-furyl)-1,2,4-triazole. M.P. 135.5137.5 C. (Found (percent): C, 58.1; H, 7.1; N, 27.5. Calc. for C H N O (206.1) (percent): C, 58.2; H, 6.9; N, 27.2.)

. 4 (b) Preparation of 3-acetylethylamino-4-ethyl-5- (2-furyl)-1,2,4-triazole (c) Preparation of 4-ethyl-3-ethylarnino-5-(S-nitro-Z- fury )-1,2,4-triazole 9.2 g. (0.037 mole) of 3-acetylethylamino-4-ethyl-5 (2-furyl)-l,2,4-triazole were dissolved in 29 ml. of cone. sulfuric acid. 3.4 ml. of cone. nitric acid were added in a dropwise manner to the sulfuric acid solution at -5 to 2 C. over a 30 minute period. The solution obtained was poured out on ice. 2.6 g. of solids precipitated. Upon neutralization of the acid solution another 3.8 g. of solids precipitated. The solids were combined and boiled with 20 ml. of 2 N hydrochloric acid for 1% hours. Upon neutralization, 2.1 g. of 4-ethyl-3-ethylamino-5-(S-nitro- 2-furyl)-l,2,4-triazole precipitated in the form of crystals melting at 183186 C.

EXAMPLE 3 The following example illustrates an alternative method of synthesizing 3-amino-4-methyl-5-(5-nitro-2-furyl)- 1,2,4-triazole.

2.43 ml. of cone. HNO was. added dropwise to 5 ml.-of conc. H 50 at 0 C. This nitration mixture was added dropwise to a solution of 3-amino-4-methy1-5-(2-furyl)- 1,2,4-triazole in 25 ml. of cone. H 30 at 0 C. The a ddition took 15 min. and the solution was stirred for another 45 min. and then poured on ice. The sulphate salt of 3-amino 4 methyl5-(5-nitro-2-furyl)-1,2,4-triazole precipitated. The free base was obtained by dissolving the salt in ml. of 2 M HCl and then neutralizing the solution with 5 M NH OH. 4.5 g. (71%) of 3-amino-4- methyl 5 (5-nitro-2-furyl)-1,2,4-triazole was obtained. M.P. 282282.5 C. (decomp.).

The advantage of this method is that it gives a higher yield, a purer product and represents a simplified Way of synthesis because no acetylation and deacetylation are required.

UTILITY It has been discovered that the compounds of the Formula I possess a high order of therapeutic activity when administered to hosts infected with various pathogenic microorganisms at dosages causing no mainifestation of toxic effect.

The novel compounds of the Formula I may be used either as such or as non-toxic salts thereof with organic or inorganic bases for the combatting of infections. The compounds not substituted with an acyl group possess ampholytic properties and may be used also in the form of non-toxic salts with organic and inorganic acids.

The antimicrobial effect on different microorganims of one substance according to the invention is evident from the following table specifying the lowest concentration of the substance in micrograms per ml. of substrate causing a complete growth inhibition of some of the microorganisms. The following substance was tested:

3-amino-4-methyl-5-(5-nitro-2-furyl)-1,2,4-triazo1e HCCH N-N H II II II OzNC CNH2 TABLE 1 M. tuberculosis 12.5 Staphylococcus aureus 6.312.5 E. coli 1.6

On oral application, the substances will be absorbed and excreted in the urine which makes them utilizible as TABLE 2 Inhibition zone diameter in mm. obtained by urine collected after:

-1 hour 25 1-2 hours 32 2-4 hours 28 4-6 hours 20 The compounding and formulating of the new compounds in dosage forms capable of ready administration is easily accomplished in accordance with accepted practice in the art. Tablets, suspensions, capsules and like dosage forms containing the new compounds in desired quantity can be readily prepared using excipients, adjuvants and carriers conventionally employed.

What we claim is:

1. A compound selected from the group consisting of compounds of the formula wherein R represents lower alkyl; R is a member selected from the group consisting of hydrogen and lower alkyl; and R is a member selected from the group consisting of hydrogen, lower alkyl, and radicals of the formula COR wherein R is a member selected from the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, and halogen-substituted alkyl containing from 1 to 3 carbon atoms, and therapeutically useful salts thereof.

2. 3 amino 4 methyl-5-(5-nitro-2-fury1)-1,2,4-triazole.

3. 3 acetylamino 4 methyl-5-(5-nitro-2-furyl)-1,2, 4-triazole.

4. 4 ethyl 3 ethylamino-5-(5-nitro-2-furyl)-1,2,4- triazole.

5. A therapeutically useful salt of the compound set forth in claim 2.

6. A therapeutically useful salt of the compound set forth in claim 3.

7. A therapeutically useful salt of the compound set forth in claim 4.

8. The compound of claim 1 wherein R is a member selected from the group consisting of methyl, ethyl, npropyl, and isopropyl.

9. The compound of claim 1 wherein R and R are hydrogen.

10. The compound of claim 1 wherein R is a member selected from the group consisting of formyl, acetyl, propionyl, chloroacetyl, dichloroacetyl, 2-chloropropionyl, and bromoacetyl.

Wagner et al.: Synthetic Organic Chemistry (New York, 1953), pp. 746-9.

ALTON D. ROLLINS, Primary Examiner U.S. Cl. X.R. 

